T-helper 2 cytokines, transforming growth factor ß1, and eosinophil products induce fibrogenesis and alter muscle motility in patients with eosinophilic esophagitis.

BACKGROUND & AIMS: Patients with eosinophilic esophagitis (EoE) often become dysphagic from the combination of organ fibrosis and motor abnormalities. We investigated mechanisms of dysphagia, assessing the response of human esophageal fibroblasts (HEFs), human esophageal muscle cells (HEMCs), and esophageal muscle strips to eosinophil-derived products. METHODS: Biopsy specimens were collected via endoscopy from the upper, middle, and lower thirds of the esophagus of 18 patients with EoE and 21 individuals undergoing endoscopy for other reasons (controls). Primary cultures of esophageal fibroblasts and muscle cells were derived from 12 freshly resected human esophagectomy specimens. Eosinophil distribution was investigated by histologic analyses of full-thickness esophageal tissue. Active secretion of EoE-related mediators was assessed from medium underlying mucosal biopsy cultures. We quantified production of fibronectin and collagen I by HEF and HEMC in response to eosinophil products. We also measured the expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 by, and adhesion of human eosinophils to, HEFs and HEMCs. Eosinophil products were tested in an esophageal muscle contraction assay. RESULTS: Activated eosinophils were present in all esophageal layers. Significantly higher concentrations of eosinophil-related mediators were secreted spontaneously in mucosal biopsy specimens from patients with EoE than controls. Exposure of HEFs and HEMCs to increasing concentrations of eosinophil products or co-culture with eosinophils caused HEFs and HEMCs to increase secretion of fibronectin and collagen I; this was inhibited by blocking transforming growth factor ß1 and p38 mitogen-activated protein kinase signaling. Eosinophil binding to HEFs and HEMCs increased after incubation of mesenchymal cells with eosinophil-derived products, and decreased after blockade of transforming growth factor ß1 and p38 mitogen-activated protein kinase blockade. Eosinophil products reduced electrical field-induced contraction of esophageal muscle strips, but not acetylcholine-induced contraction. CONCLUSIONS: In an analysis of tissues samples from patients with EoE, we linked the presence and activation state of eosinophils in EoE with altered fibrogenesis and motility of esophageal fibroblasts and muscle cells. This process might contribute to the development of dysphagia.

Lynch syndrome-associated neoplasms: a discussion on histopathology and immunohistochemistry.

It was a century ago that Warthin, a pathologist, first described the clinical condition now known as Lynch syndrome. One hundred years later, our understanding of this syndrome has advanced significantly. Much of the progress took place over the last 25 years and was marked by a series of interacting developments from the disciplines of clinical oncology, pathology, and molecular genetics, with each development serving to guide or enhance the next. The advancement of our understanding about the pathology of Lynch syndrome associated tumors exemplifies such intimate interplay among disciplines. Today, accumulative knowledge has enabled surgical pathologists to detect tumors that are likely to be associated with Lynch syndrome, and the pathologist is playing an increasingly more important role in the care of these patients. The pathologist's ability is afforded primarily by information gained from tumor histopathology and by DNA mismatch repair protein immunohistochemistry. It is therefore pertinent both for the pathologists to accurately ascertain this morphologic information, and for all that are involved in the care of these patients to thoroughly understand the implications of such information. This article provides an overview of the development of histopathology and immunohistochemistry in Lynch syndrome-associated tumors, particularly in colorectal and endometrial cancers, and outlines the issues and current status of these specific pathologic aspects in not only the major tumors but also those less commonly seen or only newly reported in Lynch syndrome patients.

Isolated supraclavicular lymph node metastasis in pancreatic adenocarcinoma: a report of three cases and review of the literature.

CONTEXT: Supraclavicular lymph nodes represent a rare site of metastasis in pancreatic cancer. We report three cases of pancreatic adenocarcinoma with metastases to supraclavicular lymph nodes. CASE REPORT: A 51-year-old male was diagnosed with locally advanced pancreatic adenocarcinoma on computed tomography (CT) scan. He was recommended neoadjuvant chemotherapy followed by chemoradiation therapy. However, positron emission tomography (PET)/CT scans and subsequent fine needle aspiration cytology showed supraclavicular lymph node metastasis. The patient received systemic chemotherapy for metastatic pancreatic adenocarcinoma. The second patient, a 66-year-old female with pancreatic adenocarcinoma, underwent pancreaticoduodenectomy and was found to have peripancreatic lymph node involvement. She received adjuvant chemotherapy and was followed-up with surveillance CT scans, which did not reveal any metastasis. However, the patient complained of neck swelling. PET/CT scan and biopsy revealed supraclavicular lymph node metastasis from a pancreatic adenocarcinoma primary. The third patient, a 79-year-old male with a past history of thyroid carcinoma who was treated with partial thyroidectomy, developed neck swelling 4 years after his surgery. Fine needle aspiration cytology was consistent with known papillary thyroid carcinoma. Staging evaluations revealed a pancreatic mass for which he underwent subtotal pancreatectomy and splenectomy. Histopathology revealed grade 3 pancreatic adenocarcinoma. Excisional biopsy of a supraclavicular lymph node showed metastatic pancreatic adenocarcinoma. PET/CT results were consistent with these findings. CONCLUSION: In patients with pancreatic adenocarcinoma, supraclavicular lymph node metastasis represents an uncommon, but clinically significant finding that can lead to changes in treatment planning. PET imaging represents a valuable tool in the detection and follow up of these patients.

Treatment of gastric antral vascular ectasia (watermelon stomach) with endoscopic band ligation.

BACKGROUND: Gastric antral vascular ectasia (GAVE) is characterized by mucosal and submucosal vascular ectasia causing recurrent GI hemorrhage. Treatment of GAVE with endoscopic thermal therapy (ETT) requires multiple sessions for destruction of vascular ectasia and control of bleeding. Endoscopic band ligation (EBL) has become the standard treatment of varices because it effectively obliterates the submucosal plexus of esophageal varices with an acceptably low rate of complications. Additionally, EBL has been used for control of bleeding from other GI vascular lesions. In patients with GAVE and recurrent GI hemorrhage, EBL may offer an alternative to ETT for treatment of large areas of diseased mucosa and submucosa. OBJECTIVE: Our purpose was to compare EBL (n = 9) with ETT (n = 13) for the treatment of bleeding from GAVE. DESIGN: Observational comparative study. PATIENTS: Patients with gastric antral vascular ectasia with occult or overt bleeding. SETTING: Mayo Clinic Arizona, a multispecialty academic medical center. INTERVENTION: EBL or ETT with argon plasma coagulation or electrocautery. MAIN OUTCOME AND MEASUREMENTS: Number of treatments to cessation of bleeding and posttreatment hemoglobin, hospitalization, and transfusion requirement. RESULTS: There were no significant differences in the demographics, clinical presentation, associated portal hypertension, or mean hemoglobin values or the mean number of transfusions or hospitalizations between the 2 groups before treatment. Four patients in the EBL group had failed prior ETT. Compared with ETT, in exploratory statistical testing EBL had a significantly higher rate of bleeding cessation (67% vs 23%, P = .04), fewer treatment sessions required for cessation of bleeding (1.9 vs 4.7, P = .05), a greater increase in hemoglobin values (2.8 g/dL vs 0.9 g/dL, P = .05), a greater decrease in transfusion requirements (-12.7 vs -5.2, P = .02), and a greater decrease in hospital admissions (-2.6 vs -0.5, P = .02) during the follow-up period. Analysis of covariance showed significantly superior efficacy of EBL for cessation of bleeding, postprocedure transfusion, and hospitalization. One patient in the EBL group had postprocedure emesis and 1 in the ETT group had immediate post procedure bleeding. All patients in the EBL group had complete mucosal healing with minimal residual GAVE at follow-up endoscopy failed post-EBL. CONCLUSIONS: Our initial experience suggests that EBL is superior to ETT for the management of GAVE. EBL required fewer treatment sessions for control of bleeding, had higher rates for cessation of bleeding, had a reduction in hospitalizations and transfusion requirements, and allowed for a significant increase in hemoglobin values.

Interobserver agreement in hepatitis C grading and staging and in the Banff grading schema for acute cellular rejection: the "hepatitis C 3" multi-institutional trial experience.

CONTEXT: Establishing adequate interobserver agreement is crucial not only for standardization of patient care but also to ensure validity of findings in multi-institutional trials. OBJECTIVE: To evaluate interobserver agreement in assessing chronic hepatitis C (HCV) and acute cellular rejection (ACR) among 17 hepatopathologists involved in the "Hepatitis C 3" trial. DESIGN: The trial is a randomized multicenter (17 institutions) study involving 312 patients undergoing transplantation for HCV. Patients are randomized to 3 treatment arms. For final data analysis, all biopsy specimens are reviewed by a central pathologist (G.J.N.). Recurrence of HCV is evaluated according to the Batts and Ludwig schema. The 1997 Banff schema is used to evaluate ACR. To assess interobserver agreement, hematoxylin-eosin-stained sections from 11 liver biopsy specimens (6 HCV and 5 ACR) were sent by the central pathologist to 16 local pathologists from 13 institutions. Statistical analysis was performed on raw ACR/HCV data as well as data grouped according to clinically significant primary endpoint cutoffs. RESULTS: Statistically significant agreement was found among all participating pathologists (P < .001). On kappa analysis, the degree of agreement was rated "moderate" for HCV grade and stage and ACR global grading (kappa = 0.30, 0.33, and 0.37, respectively). Interobserver agreement was weaker for rejection activity index scoring of ACR (kappa = 0.15). A stronger degree of agreement was found when scores were grouped based on endpoint cutoffs (kappa = 0.76 "almost perfect" for HCV and 0.62 "substantial" for ACR). CONCLUSIONS: An overall statistically significant interobserver agreement was found among 17 pathologists using the 1997 Banff schema and the Batts and Ludwig schema.